HMGB1 is a potent proinflammatory mediator expressed abundantly in chronic synovitis

Aim

To dissect the role of the endogenous, cytokine-like protein high mobility group1 protein (HMGB1) in arthritis, we set out to investigate the presence of HMGB1 in synovial biopsies from rats with adjuvant arthritis and in synovial biopsies and synovial fluid samples from patients with active RA.

Background

HMGB1 is a DNA-binding, non-histone, nuclear protein present in all nucleated cells. Previous results have demonstrated that HMGB1 is released from the cytoplasm of activated monocytes and macrophages and that extracellular HMGB1 is a potent inducer of production of proinflammatory cytokines in monocytes and macrophages. Furthermore, anti-HMGB1 treatment inhibits LPS-induced lethality in sepsis in mice.

Methods

Presence of released HMGB1 in synovial membranes from arthritic rats and synovial membrane biopsies from RA patients, were detected by immunohistochemistry. Analysis of HMGB1 in synovial fluid was performed by western blotting.

Results

In rat ankle joint specimens obtained at the onset of arthritis, as well as in the chronic stage of the disease, we detected cytoplasmic HMGB1 in macrophage/monocyte-like cells in the synovial membrane as well as in synovial fluid. The levels of cytoplasmic expression was higher at later stages of disease. A similar picture was obtained when immunohistochemical stainings were performed on synovial biopsies from RA patients. Analysis of synovial fluid samples from RA patients revealed high levels of released HMGB1. Intra-articular rHMGB1 injections in rats caused erosive synovitis.

Conclusion

HMGB1 is a newly identified proinflammatory molecule, now shown to be present in arthritic joints of both RA patients and rats with adjuvant arthritis. With reference to the previously demonstrated capacity of HMGB1 to stimulate the production of TNF and IL-1β, we speculate that HMGB1 could be of importance in the pathogenesis of arthritis.